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Fenofibrate but not fenofibric acid inhibits 11beta-hydroxysteroid dehydrogenase 1 in C2C12 myotubes

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Abstract

Fibrates and WY-14643 are widely used as lipid-lowering drugs via modulation of peroxisome proliferator-activated receptor alpha (PPAR α) for the treatment of a wide range of metabolic disorders. Here, to address the question whether PPAR α agonists can affect the enzymatic activity of 11beta-hydroxysteroid dehydrogenase1 (11β-HSD1), we tested fibrates and WY-14643 for the inhibition of cellular 11β-HSD1 activity in C2C12 myotubes. Only fenofibrate but not fenofibric acid, an active agonist of PPAR α, exerted a potent inhibitory activity in the cell based assay, showing an IC50 of 1.6 μM. Furthermore, we also demonstrated that the masking of carboxyl group in fenofibric acid via esterification or amidation was required for the inhibitory potencies of fenofibric acid derivatives against 11β-HSD1. In this presentation, we propose that fenofibrate can display a pharmacodynamic role distinct from fenofibric acid through masking of carboxyl group in fenofibric acid.

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References

  1. Dayspring T, Pokrywka G (2006) Fibrate therapy in patients with metabolic syndrome and diabetes mellitus. Curr Atheroscler Rep 8:356–364

    Article  CAS  PubMed  Google Scholar 

  2. Latruffe N, Cherkaoui Malki M, Nicolas-Frances V, Clemencet MC, Jannin B, Berlot JP (2000) Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases. Biochem Pharmacol 60:1027–1032

    Article  CAS  PubMed  Google Scholar 

  3. Hermanowski-Vosatka A, Gerhold D, Mundt SS, Loving VA, Lu M, Chen Y, Elbrecht A, Wu M, Doebber T, Kelly L, Milot D, Guo Q, Wang PR, Ippolito M, Chao YS, Wright SD, Thieringer R (2000) PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver. Biochem Biophys Res Commun 279:330–336

    Article  CAS  PubMed  Google Scholar 

  4. Nakano S, Inada Y, Masuzaki H, Tanaka T, Yasue S, Ishii T, Arai N, Ebihara K, Hosoda K, Maruyama K, Yamazaki Y, Shibata N, Nakao K (2007) Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3–L1 adipocytes. Am J Physiol Endocrinol Metab 292:E1213–E1222

    Article  CAS  PubMed  Google Scholar 

  5. Srivastava RA (2009) Fenofibrate ameliorates diabetic and dyslipidemic profiles in KKAy mice partly via down-regulation of 11beta-HSD1, PEPCK and DGAT2. Comparison of PPARalpha, PPARgamma, and liver x receptor agonists. Eur J Pharmacol 607:258–263

    Article  CAS  PubMed  Google Scholar 

  6. Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 58:782–797

    Article  CAS  PubMed  Google Scholar 

  7. Brindley DN (1995) Role of glucocorticoids and fatty acids in the impairment of lipid metabolism observed in the metabolic syndrome. Int J Obes Relat Metab Disord 19(Suppl 1):S69–S75

    PubMed  Google Scholar 

  8. Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD (2002) Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 51:1066–1075

    Article  CAS  PubMed  Google Scholar 

  9. Cho YS, Kim CH, Cheon HG (2009) Cell-based assay for screening 11beta-hydroxysteroid dehydrogenase 1 inhibitors. Anal Biochem 392:110–116

    Article  CAS  PubMed  Google Scholar 

  10. Sandeep TC, Yau JL, MacLullich AM, Noble J, Deary IJ, Walker BR, Seckl JR (2004) 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101:6734–6739

    Article  CAS  PubMed  Google Scholar 

  11. Kuwabara K, Murakami K, Todo M, Aoki T, Asaki T, Murai M, Yano J (2004) A novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay mice. J Pharmacol Exp Ther 309:970–977

    Article  CAS  PubMed  Google Scholar 

  12. Shimomura K, Shimizu H, Ikeda M, Okada S, Kakei M, Matsumoto S, Mori M (2004) Fenofibrate, troglitazone, and 15-deoxy-Delta12, 14-prostaglandin J2 close KATP channels and induce insulin secretion. J Pharmacol Exp Ther 310:1273–1280

    Article  CAS  PubMed  Google Scholar 

  13. Thomas J, Bramlett KS, Montrose C, Foxworthy P, Eacho PI, McCann D, Cao G, Kiefer A, McCowan J, Yu KL, Grese T, Chin WW, Burris TP, Michael LF (2003) A chemical switch regulates fibrate specificity for peroxisome proliferator-activated receptor alpha (PPARalpha) versus liver X receptor. J Biol Chem 278:2403–2410

    Article  CAS  PubMed  Google Scholar 

  14. Rath NP, Haq W, Balendiran GK (2005) Fenofibric acid. Acta Crystallogr C 61:o81–o84

    Article  PubMed  Google Scholar 

  15. Caldwell J (1989) The biochemical pharmacology of fenofibrate. Cardiology 76(Suppl 1):33–41 (discussion 41–44)

    Article  PubMed  Google Scholar 

  16. Boden G, Homko C, Mozzoli M, Zhang M, Kresge K, Cheung P (2007) Combined use of rosiglitazone and fenofibrate in patients with type 2 diabetes: prevention of fluid retention. Diabetes 56:248–255

    Article  CAS  PubMed  Google Scholar 

  17. Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19:26–37

    Article  CAS  PubMed  Google Scholar 

  18. Szustakowski JD, Lee JH, Marrese CA, Kosinski PA, Nirmala NR, Kemp DM (2006) Identification of novel pathway regulation during myogenic differentiation. Genomics 87:129–138

    Article  CAS  PubMed  Google Scholar 

  19. Potter PM, Wadkins RM (2006) Carboxylesterases-detoxifying enzymes and targets for drug therapy. Curr Med Chem 13:1045–1054

    Article  CAS  PubMed  Google Scholar 

  20. Li P, Callery PS, Gan LS, Balani SK (2007) Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab Dispos 35:1203–1208

    Article  CAS  PubMed  Google Scholar 

  21. Khan D, Gilmer JF, Carolan CG, Gaynor JM, Ryder SA (2008) Pharmacological effects of a novel isosorbide-based butyrylcholinesterase inhibitor. Chem Biol Interact 175:231–234

    Article  CAS  PubMed  Google Scholar 

  22. Satoh T, Hosokawa M (1998) The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol 38:257–288

    Article  CAS  PubMed  Google Scholar 

  23. Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, Marnett LJ (2000) Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 97:925–930

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by the Center for Biological Modulators of the 21st Century Frontier R&D Program, Ministry of Education, Science and Technology, South Korea and by Basic Research Program, KRICT, South Korea. This work was also supported by grant (T3021A to HSJ) from Korea Basic Science Institute.

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Authors and Affiliations

  1. Pharmacology Research Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, South Korea

    Chi Hyun Kim & Young Sik Cho

  2. Division of Electron Microscopic Research, Korea Basic Science Institute, 113 Gwahangno, Yusung-gu, Daejeon, 305-333, South Korea

    Chi Hyun Kim

  3. Metabolic Syndrome Therapeutic Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, South Korea

    Ravirala Ramu

  4. Drug Discovery Platform Technology Team, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, South Korea

    Jin Hee Ahn & Myung Ae Bae

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  1. Chi Hyun Kim
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  2. Ravirala Ramu
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  3. Jin Hee Ahn
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Correspondence to Young Sik Cho.

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Kim, C.H., Ramu, R., Ahn, J.H. et al. Fenofibrate but not fenofibric acid inhibits 11beta-hydroxysteroid dehydrogenase 1 in C2C12 myotubes. Mol Cell Biochem 344, 91–98 (2010). https://doi.org/10.1007/s11010-010-0532-4

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  • DOI: https://doi.org/10.1007/s11010-010-0532-4

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